1. Field of the Invention
The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to a process for making the compounds and to the use of the compounds in therapy. More particularly, it relates to certain substituted 1H-pyrazolo[3,4-b]pyridine compounds useful for inhibiting Raf kinase and for treating disorders mediated thereby.
2. Description of the State of the Art
The Raf/MEK/ERK pathway is critical for cell survival, growth, proliferation and tumorigenesis. Li, Nanxin, et al. “B-Raf kinase inhibitors for cancer treatment.” Current Opinion in Investigational Drugs. Vol. 8, No. 6 (2007): 452-456. Raf kinases exist as three isoforms, A-Raf, B-Raf and C-Raf. Among the three isoforms, studies have shown that B-Raf functions as the primary MEK activator. B-Raf is one of the most frequently mutated genes in human cancers. B-Raf kinase represents an excellent target for anticancer therapy based on preclinical target validation, epidemiology and drugability.
Small molecule inhibitors of B-Raf are being developed for anticancer therapy. Nexavar® (sorafenib tosylate) is a multikinase inhibitor, which includes inhibition of B-Raf, and is approved for the treatment of patients with advanced renal cell carcinoma and unresectable hepatocellular carcinoma. Other Raf inhibitors have also been disclosed or have entered clinical trials, for example SB-590885, RAF-265, PLX-4032 and XL-281. Other B-Raf inhibitors are also known, see for example, U.S. Patent Application Publication 2006/0189627, U.S. Patent Application Publication 2006/0281751, U.S. Patent Application Publication 2007/0049603, International Patent Application Publication WO 2007/002325 and International Patent Application Publication WO 2007/002433.
Pyrazolopyridines are known, see for example, International Patent Application Publication WO 03/068773 and International Patent Application Publication WO 2007/013896.
Kinase inhibitors are known, see for example, International Patent Application Publication WO 2005/062795.
International Patent Application Publication WO 2008/079906 and International Patent Application Publication WO 2008/079909 also disclose kinase inhibitors.
International Patent Application Publication WO 2006/066913, International Patent Application WO 2008/028617 and International Patent Application Publication WO 2009/012283 also disclose kinase inhibitors.